The Molecular Imaging Branch (MIB) aims to exploit positron emission tomography (PET) as a radiotracer imaging technique for investigating neuropsychiatric disorders, such as autism, depression, addiction, schizophrenia and Alzheimer's disease. Fundamental to the mission of the MIB is the development of novel radioactive probes (radiotracers) that can be used with PET to deliver new and specific information on molecular entities and processes in living animal or human brain (e.g., regional neuroreceptor densities, neurotransmitter synthesis, enzyme concentrations, amyloid deposition, drug efflux from brain). PET is a uniquely powerful and sensitive imaging modality for such purposes when successfully coupled to appropriate PET radiotracers. The chemical development of new radiotracer types is the key to exploiting the full potential of PET in neuropsychiatric research. Such radiotracer development is widely recognized as being a highly challenging and demanding scientific task. In fact, the number of potentially interesting imaging targets far exceeds the range of available and useful radiotracers. Within MIB, our laboratory, the PET Radiopharmaceutical Sciences Section, places a concerted effort on all medicinal chemistry and radiochemical aspects of PET radiotracer discovery. This research activity has some parallels with drug discovery in terms of required effort and risk, because successful PET probes must fulfill a difficult-to-satisfy range of chemical, pharmacological and biological criteria. In support of our mission, our laboratories are equipped to perform medicinal chemistry and automated radiochemistry with positron-emitting carbon-11 (t1/2 = 20 min) and fluorine-18 (t1/2 = 110 min). These two short-lived radioisotopes are available to us daily from the adjacent cyclotrons of the NIH Clinical Center (Chief Dr. P. Herscovitch). We are developing novel probes for studying many different brain proteins that are implicated in neuropsychiatric disorders. Examples are cannabinoid (CB-1), serotonin (5-HT1A, 5-HT4), TSPO (formerly known as PBR), nociceptin (NOP), histamine-H3, oxytocin and glutamate (mGlu1, mGlu5)receptors, efflux transporters (P-gp, BCRP) and protein deposits such as beta-amyloid and tau fibrils. Our Section interacts seamlessly with the Imaging Section of our Branch (Chief: Dr. R.B. Innis) for early evaluation of potential radiotracers in animals. Subsequent PET research in human subjects is also performed in collaboration with the Imaging Section under Food and Drug Administration oversight through 'exploratory' or full investigational new drug applications (expINDs or INDs, respectively). Our research has provided a stream of new radiotracers for TSPO, CB-1, mGluR5, NOP and P-gp for brain imaging in human subjects in support of clinical research and drug development. Two radiotracers (C-11PBR28 and F-18FBR), developed successfully for TSPO imaging, are being applied for the investigation of brain inflammatory conditions in response to neurological insults e.g., traumatic brain injury, stroke, epilepsy and neurodegeneration (Alzheimer's disease). Other institutions (e.g., Karolinska Institutet) have also taken up the use of these radiotracers. An interesting and unexpected finding is that healthy human subjects have one or both of two different forms of TSPO that interact differently with C-11PBR28. New less discriminatory TSPO radioligands would therefore be useful and are under development. One of these will soon be evaluated in hunan subjects. CB-1 receptors are the brain proteins acted upon by cannabis. Our new CB-1 radiotracers (11CMePPEP and F-18FMPEP) find application for the study of drug addiction, including cannabis use and alcoholism. Indeed, a recent study from our Branch with 11CMePPEP reveals definite changes in brain CB1 receptors in response to cannabis or alcohol. The use of C-11MEPPEP is also being taken up elsewhere. We are evaluating a further CB1 receptr radiotracer with PET in human subjects to assess its relative merits. Our research has also led to a radiotracers that is useful for studying CB1 receptors with an alternative imaging modality (SPECT). Our GluR5 radiotracers(F-18SP203, C-11SP203) are expected to have value for the study of Fragile X syndrome, other autism conditions, addiction, and schizophrenia. They may also expedite drug discovery for conditions such as Fragile X, since potentially they may be used in drug-receptor occupancy (RO) studies to determine dosing regimes to be used in clinical trials. The imaging of the function of the drug efflux pump (e.g., P-gp) at the blood-brain barrier is an area of interest in our laboratory with relevance to drug development for neuropsychiatric disorders. We have developed a much improved radiotracer, named C-11dLop, for this purpose. C-11dLop may have value for assessing the role of efflux pumps in Alzheimer's disease and other neurodegenerative disorders (e.g., Parkinson's disease). A radiotracer for imaging P-gp density is sought in addition to our radiotracer of function. Radiotracers for other efflux pumps, such as BCRP are also sought, as are radiotracers capable of measuring increased efflux transporter action. Some of our radiotracers are likely to have value for diseases that present outside the brain. Thus, the TSPO radiotracers may have value for the study of inflammation in the periphery (e.g., as occurs in atherosclerosis), and the P-gp radiotracer for the study of cancer (especially multi-drug resistance). Methodology underpinning our radiotracer development was also advanced in areas such as the development of new synthetic methods, new radiolabeling procedures, and the application of micro-reactors to the miniaturization of radiochemistry. We have combined the use of microfluidics with a new F-18 labeling strategy to great effect, thereby expanding the number and type of candidate F-18 labeled radiotracers that may be produced. Such advances are vital for facilitating radiotracer applications. New analytical methods, based on for example liquid chromatography coupled to mass spectrometry (LC-MS), have also been developed and exploited to understand the biochemical fate of radiotracers in living systems. This information is needed to fully understand the results from PET experiments and to derive meaningful output measures, such as brain receptor concentrations. Sensitive LC-MS/MS has been introduced for the measurement of radiotracer half-life and specific radioactivity, and is also being investigated for the measurement of radiotracer concentration in blood following intravenous administration. The use of LC-MS/MS avoids the need to measure fast-decaying radioactivity. Productive collaborations have been established with external academic chemistry and medicinal chemistry laboratories, nationally and internationally, and also with pharmaceutical companies through CRADAs (Cooperative Research and Development Agreements) and the Biomarker Consortium of the Foundation for NIH. Productive collaborations also exist with other centers working with PET and its associated radiochemistry and radiotracer development. The laboratory is active in training new scientists for this field at all levels. In addition, we produce some useful radiotracers that have been developed elsewhere for PET investigations in animal or human subjects e.g., C-11CUMI (5-HT1A receptor imaging), and C-11rolipram (PDE4 enzyme imaging). The production of such radiotacers for use in human subjects also complies with (Food and Drug Administration) FDA requirements under expINDS or INDs. Each PET experiment with any radiotracer requires a radiosynthesis of the radiotracer on the same day, and hence radiotracer production is a regular activity. About 300 productions are performed annually